Successful Application of Tocilizumab in a Patient With Neoadjuvant Immunochemotherapy‐Induced Cytokine Release Syndrome

ABSTRACT Background The expansion of preoperative immunochemotherapy has led to an increase in the number of patients with lung cancer receiving immune checkpoint inhibitors (ICIs). Therefore, oncologists should manage a variety of immune‐related adverse events (irAEs). One of the rare, life‐threatening, and recently proposed irAEs is cytokine release syndrome (CRS). Although the standard treatment of irAE is systemic administration of steroids, it has been suggested that tocilizumab may be an effective treatment option for CRS. Case This case describes a 69‐year‐old man with stage IIIA lung adenocarcinoma who received chemotherapy and nivolumab, which is an ICI, as neoadjuvant immunochemotherapy. After the first administration, the patient developed severe skin rash, fever, and arthralgia. We suspected irAEs and administered systemic steroids. However, fever and arthralgia did not improve, although the skin rash disappeared. These were also significant challenges for surgery. Noting the elevated levels of inflammatory cytokines, we consulted a rheumatologist. Finally, we decided to terminate neoadjuvant therapy after one cycle and administer tocilizumab. Tocilizumab dramatically improved the patient's symptoms and allowed him to undergo radical surgery. Pathological findings revealed that the patient achieved a major pathological response. Conclusion This indicates the potential effectiveness of early tocilizumab administration for ICI‐induced CRS, even in mild cases.


| Introduction
Immune checkpoint inhibitors (ICIs) have been proven effective against various cancers, including lung cancer.Furthermore, the CheckMate 816 trial showed that the neoadjuvant nivolumab in combination with chemotherapy improved clinical outcomes compared to chemotherapy alone in patients with resectable non-small cell lung cancer [1].
However, ICIs can activate the immune system and cause immune-related adverse events (irAEs) in multiple organs, some of which can be life-threatening [2].
Cytokine release syndrome (CRS), although a rare irAE, can be lethal.
determine superiority of chemotherapy plus nivolumab and ipilimumab over chemotherapy plus pembrolizumab in advanced or recurrent non-small cell lung cancer (negative or unknown driver gene mutation).The enrollment began in April 2021 but was terminated in March 2023 due to several deaths related to unanticipated adverse events in the combined use of nivolumab plus ipilimumab.Among treatment-related deaths, three were diagnosed with CRS [3].
CRS is difficult to diagnose because of its rare occurrence and clinically nonspecific symptoms and signs [4][5][6].
In chimeric antigen receptor (CAR) T-cell therapy-induced CRS cases, tocilizumab has been widely used for the treatment of any severity in recent years; however, data on the appropriate timing of its administration are scarce [7,8].On the other hand, there are a few cases that tocilizumab plus corticosteroid treatment was effective for severe CRS induced by ICIs [9,10].
Herein, we report a case of neoadjuvant immunochemotherapyinduced steroid-resistant CRS that responded to tocilizumab treatment in addition to corticosteroid monotherapy.Pathological findings revealed that the patient achieved a major pathological response (MPR), defined as having less than 10% of viable tumor cells remaining in the primary tumor, following radical surgery.

| Case Presentation
A 69-year-old man was referred to our hospital with a lesion in the lower left lung lobe and swollen ipsilateral hilar and subtracheal lymph nodes, as observed in a positron emission tomography/computed tomography (CT) scan.He had been a smoker for 50 years and had no major medical history.
Bronchoscopy was performed on the lung lesion, which revealed lung adenocarcinoma, strongly positive for programmed deathligand 1 (tumor proportion score ≥50%) and negative for driver mutations.
The clinical diagnosis was cT2bN2M0, stage IIIA lung adenocarcinoma.
However, just 21 days after the first cycle of immunochemotherapy, the patient developed grade 3 skin rash, grade 1 fever, and grade 1 arthralgia as per the Common Terminology Criteria for Adverse Events criteria.
We suspected that the cause was noninfectious because a CT scan revealed no signs of infection, and the results of blood and urine culture tests were both negative.As the CT scan showed shrinkage of the primary lung lesion and lymph nodes (Figure 1), we decided to terminate neoadjuvant therapy after one cycle, and radical surgery was planned when the skin rash was controllable.
We considered irAEs and consulted a dermatologist regarding skin rash.In line with the dermatologist's recommendation, we started prednisolone treatment at a dosage of 60 mg (1 mg/kg body weight) along with the most potent steroid ointment.
As the skin rash improved promptly, the dose was tapered off by 20%-30% per few days and a maintenance dose of 7.5 mg was started on day 30 after the administration of steroids.
Although the skin rash had resolved at that point, the patient still had slight fever, arthralgia, and grade 2 anemia (Hb 8.7 g/dL), which posed obstacles to the surgery.
We revisited the patient's pathophysiology again.After gastrointestinal bleeding was ruled out by upper endoscopy and colonoscopy, we emphasized the presence of elevated inflammatory cytokines in the blood test, including a C-reactive protein (CRP) level of 7.4 mg/dL, a ferritin level of 708 ng/mL, and an interleukin-6 (IL-6) level of 61.2 pg/mL.As a result, we sought consultation with a rheumatologist.

The tumor at initial examination After 1 course of Nivolumab and chemotherapy
After consultation with the the patient was diagnosed ICI-induced CRS because the infection was negative, prolonged fever and arthralgia were observed, anemia appeared, and blood tests showed elevated inflammatory cytokines.
Although the patient did not have hypotension or hypoxemia and had mild CRS (Grade 1 according to the American Society for Transplantation and Cellular Therapy [ASTCT] Consensus Grading [11]), he needed improvement of his general conditions to undergo surgery.
For this reason, tocilizumab administration was recommended.
The patient was treated with a subcutaneous injection of tocilizumab (162 mg, biweekly) on days 64 and 72 after the first cycle of immunochemotherapy, and the symptoms substantially improved.Moreover, the results of blood test showed significant improvement in anemia (from 8.7 to 10.0 g/dL) and CRP (from 7.4 to 0.03 mg/dL).On day 85 after the first cycle of immunochemotherapy, he underwent radical surgery, and pathological findings confirmed that residual tumor cell proportions were less than 5% in the primary lung lesion, and no malignant cells were detected in the lymph nodes (Figure 2).The patient exhibited an MPR.A brief diagram of the clinical course is shown in Figure 3.

| Discussion
In this case, the poor general condition due to CRS affected operative tolerance despite the mild severity.Following the administration of tocilizumab, there was a remarkable improvement in the patient's overall condition, thus enabling the patient to undergo radical surgery.
While ICI strongly blocks inhibitory signals that suppress Tcell activity and reactivate tumor immunity by T cells, CAR-T Fever therapy genetically engineers a patient's T to express chimeric antigen receptors that can directly recognize and target specific tumor antigens [14].Both ICI and CAR-T therapies are similar in that they reactivate tumor immunity by T cells [15].
In patients experiencing CRS after treatment with CAR-T therapy, CRS is widely treated with tocilizumab, even in mild cases [7].Although there is no established consensus on the indication and timing of tocilizumab treatment in ICI-induced CRS, tocilizumab may be considered in mild cases, as in this case.
This study had two limitations.First, in the CheckMate 816 trial, 93.8% of patients received three cycles of nivolumab plus platinum-doublet chemotherapy [1].In this case, the patient received only one cycle because of adverse effects.The longterm prognosis of the patient is unknown, although an MPR was observed after surgery.Second, the clinical course of patients with CRS remains unknown, which is a concern because CRS is a life-threatening irAE.Following surgery, oncologists should carefully observe patients while cooperating with rheumatologists.

| Conclusion
This case highlights the use of tocilizumab in addition to steroids to manage symptoms associated with ICI-induced CRS.
Although the severity of CRS was mild, he needed improvement of his general conditions to undergo surgery.Consequently, the patient's general condition improved with tocilizumab, and he achieved MPR after undergoing surgery.This implies the potential effectiveness of early administration of tocilizumab for ICIinduced CRS even in mild cases.

FIGURE 1 |
FIGURE 1 | Only one course of nivolumab and chemotherapy resulted in significant shrinkage of the tumor.

FIGURE 2 |FIGURE 3 |
FIGURE 2 | After the surgery, the residual tumor cells represented less than 5% of the primary lung lesion and were not detected in the lymph nodes.